Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff. Arch. Neurol. Psychiatry, 39:737-63, 1938. They proposed that the cause of migraine headache was vasodilatation of extracranial vessels. This view was supported by knowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT1 agonist which does not cross the blood-brain barrier, contract cephalic vascular smooth muscle and are effective in the treatment of migraine. Humphrey, et al., Ann. NY Acad. Sci., 600:587-600, 1990. Recent work by Moskowitz has shown, however, that the occurrence of migraine headaches is independent of changes in vessel diameter. Cephalalgia, 12:5-7, 1992.
Moskowitz has proposed that currently unknown triggers for pain stimulate trigeminal ganglia which innervate vasculature within the cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms involving 5-HT receptors, believed to be closely related to the 5-HT1D subtype, located on the trigeminovascular fibers. Neurology, 43(suppl. 3):S16-S20 1993.
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HT1. A human gene which expresses one of these 5-HT1 receptor subtypes, named 5-HT1F, was isolated by Kao and coworkers. Proc. Natl. Acad. Sci. USA, 90:408-412, 1993. This 5-HT1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described. The high affinity of sumatriptan at this subtype, Ki=23 nM, suggests a role of the 5-HT1F receptor in migraine.
This invention relates to novel 5-HT1F agonists which inhibit peptide extravasation due to stimulation of the trigeminal ganglia, and are therefore useful for the treatment of migraine and associated disorders.
The present invention relates to a compound of formula I: 
or a pharmaceutical acid addition salt thereof, where; 
Axe2x80x94D is CHxe2x80x94CH2 or Cxe2x95x90CH;
R1 is hydrogen or C1-C4 alkyl;
R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, or Arxe2x80x94(C1-C4 alkyl);
R3 and R4 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring; and
Ar is an optionally substituted phenyl or optionally substituted heteroaryl.
This invention also relates to a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutical acid addition salt thereof, and a pharmaceutical carrier, diluent, or excipient.
In addition, the present invention relates to a method for activating 5-HT1F receptors in mammals comprising administering to a mammal in need of such activation an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
Moreover, the current invention relates to a method for inhibiting neuronal protein extravasation comprising administering to a mammal in need of such inhibition an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
One embodiment of this invention is a method for increasing activation of the 5-HT1F receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, chronic pain, alcoholism, tobacco abuse, panic disorder, anxiety, general pain, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism, trichotillomania, trigeminal neuralgia, dental pain or temperomandibular joint dysfunction pain. The compounds of this invention are also useful as a prophylactic treatment for migraine. Any of these methods employ a compound of formula I.
The use of a compound of formula I for the activation of the 5-HT1F receptor, for the inhibition of peptide extravasation in general or due to stimulation of the trigeminal ganglia specifically, and for the treatment of any of the disorders described above, are all embodiments of the present invention.
The general chemical terms used throughout have their usual meanings. For example, the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and cyclobutyl. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes those groups listed for C1-C4 alkyl and also refers to saturated, straight, branched, or cyclic hydrocarbon chains of 5 to 6 carbon atoms. Such groups include pentyl, pent-2-yl, pent-3-yl, neopentyl, hexyl, and the like. The term xe2x80x9cC3-C8 cycloalkylxe2x80x9d refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term xe2x80x9cC2-C6 alkenylxe2x80x9d refers to mono-unsaturated straight or branched hydrocarbon chains containing from 2 to 6 carbon atoms and includes vinyl, allyl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl, 2-penten-5-yl, 3-penten-5-yl, 1-hexen-6-yl, 2-hexen-6-yl, 3-hexen-6-yl, 4-hexen-6-yl and the like.
The term xe2x80x9cC2-C6 alkynylxe2x80x9d refers to straight or branched hydrocarbon chains containing 1 triple bond and from 2 to 6 carbon atoms and includes acetylenyl, propynyl, 2-butyn-4-yl, 1-butyn-4-yl, 1-pentyn-5-yl, 2-pentyn-5-yl and the like.
The terms xe2x80x9cC1-C6 alkoxyxe2x80x9d and xe2x80x9cC1-C4 alkoxyxe2x80x9d refer respectively to a C1-C6 alkyl and C1-C4 alkyl group bonded through an oxygen atom. The term xe2x80x9cC1-C4 acylxe2x80x9d refers to a formyl group or a C1-C3 alkyl group bonded through a carbonyl moiety.
The term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo.
The term xe2x80x9cheteroarylxe2x80x9d is taken to mean an aromatic 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from: nitrogen, oxygen, and sulfur. Examples include furanyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like.
The term xe2x80x9csubstituted heteroarylxe2x80x9d is taken to mean that the heteroaryl moiety is substituted with substituents selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 acyl, and (C1-C4)n amino where n is 0, 1, or 2.
The terms xe2x80x9csubstituted phenylxe2x80x9d and xe2x80x9csubstituted phenyl(C1-C4 alkyl)xe2x80x9d are taken to mean that the phenyl moiety in either case is substituted with one substituent selected from the group consisting of halo, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, phenyl, benzoyl, C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkyl)S(O)n where n is 0, 1, or 2, (C1-C4 alkyl)2 amino, C1-C4 acyl, or two to three substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, C1-C4 alkyl, or C1-C4 alkoxy.
The term xe2x80x9camino protecting groupxe2x80x9d as used in this specification refers to substituents commonly employed to block or protect the amino functionality while reacting to other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the acetyl group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (xe2x80x9cFMOCxe2x80x9d), and the like; and like amino protecting groups. The species of amino protecting group employed is not critical so long as the derivitized amino group is stable to the condition of subsequent reactions on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1991, Chapter 7 hereafter referred to as xe2x80x9cGreenexe2x80x9d.
The term xe2x80x9cpharmaceuticalxe2x80x9d when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient.
By xe2x80x9cpharmaceutical formulationxe2x80x9d it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (a compound of formula I).
Since the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutical acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
The term xe2x80x9cacid addition saltxe2x80x9d refers to a salt of a compound of formula I prepared by reaction of a compound of formula I with a mineral or organic acid. For exemplification of pharmaceutical acid addition salts see, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, 1977.
The pharmaceutical acid addition salts of the invention are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like. The salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, tartaric acid, benzoic acid, acetic acid, and the like.
The term xe2x80x9ceffective amountxe2x80x9d means an amount of a compound of formula I which is capable of activating 5-HT1F receptors and/or inhibiting neuronal protein extravasation.
The term xe2x80x9csuitable solventxe2x80x9d refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
All enantiomers, diastereomers, and mixtures thereof, are included within the scope of the present invention. The compounds of formula I where R1 and R2 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring (indolizinyl, quinolizinyl, or 1-azabicyclo[5.4.0]undecanyl ring respectively) contain a chiral center located in that bicyclic ring. This chiral center is located at the bridghead carbon in the ring system. Such centers are designed xe2x80x9cRxe2x80x9d or xe2x80x9cS.xe2x80x9d For the purposes of the present application, the numbering system for naming the substituents around the indole ring and the R and S enantiomers are illustrated below where R1 and Ar are as defined above. 
The following group is illustrative of compounds contemplated within the scope of this invention:
5-(2-fluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-fluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2,3-difluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole methanesulfonate
5-(2,5-difluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole acetate
5-(2,6-difluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2,3,4-trifluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2,3,5-trifluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole carbonate
5-(2,3,6-trifluorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2-chlorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-chlorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2,4-dichlorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2,3,5-trichlorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole p-toluenesulfonate
5-(3-bromobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2,3-dibromobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole oxalate
5-(2,3-diiodobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(4-nitrobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-nitrobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-aminobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2,4-dimethylbenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-isopropylbenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-methoxybenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2-methylaminobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-trifluoromethoxybenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2-cyanobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-phenylbenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(2-fluoro-3-chlorobenzoylmethyl)-3-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)indole
5-(3-chlorobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,3-dichlorobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,4-dichlorobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,3,5-trichlorobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-bromobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-iodobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-methylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,3-dimethylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,4-dimethylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,5-dimethylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,6-dimethylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-ethylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-isopropylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-isopropylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,3-diisopropylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,4-diisopropylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-butylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-butylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,3-dibutylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,3,4-tributylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-pentylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-isobutylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-3-isobutylbenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-methoxybenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-methylaminobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,3-dimethylaminobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(2,5-dimethylaminobenzoylmethyl)-3-(1-methylpiperidin-4-yl)indole
5-(3-fluorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3-difluorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,4-difluorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,5-difluorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3,4-difluorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-chlorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3-dichlorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,4-dichlorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3,5-dichlorobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,5-dibromobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,6-dibromobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-iodobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3-diiodobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2-nitrobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-nitrobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3,4-trinitrobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(4-aminobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-aminobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3-diaminobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,4-diaminobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-methylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-isopropylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3-diisopropylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2-isobutylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-isobutylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3-diisobutylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3,4-diisobutylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3,5-diisobutylbenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2-methoxybenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-methoxybenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,4-dimethoxybenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,6-dimethoxybenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2-ethoxybenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2-methylaminobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(3-methylaminobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2,3-dimethylaminobenzoylmethyl)-3-[(1-methylpytrolidin-2-yl)methyl]indole
5-(3-ethylaminobenzoylmethyl)-3-[(1-methylpyrrolidin-2-yl)methyl]indole
5-(2-fluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-fluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,3-difluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,4-difluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,5-difluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,6-difluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,4,5-trifluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3,5-difluorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-chlorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-chlorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,3-dichlorobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-bromobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-bromobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,4-dibromobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,6-dibromobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-iodobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-iodobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-nitrobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-nitrobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-aminobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-aminobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-methylbenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-methylbenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2,4-dimethylbenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-isopropylbenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-isopropylbenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-methoxybenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-methoxybenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-methylaminobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(3-methylaminobenzoylmethyl)-3-(indolizidin-6-yl)indole
5-(2-thien-3-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-pyridin-4-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-furan-3-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-pyrrol-1-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-N-methylpyrrol-2-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-oxazol-2-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-isoxazol-4-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-pyrazol-4-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-imidazol-2-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-1,2,4-triazol-5-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-1,3,4-oxadiazol-2-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-1,3,4-thiadiazol-2-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-pyrimidin-5-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-pyrazin-1-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
5-(2-pyridazin-4-ylethylcarbonyl)-3-(1-methylpiperidin-4-yl)indole
While all enantiomers, diastereomers, and mixtures thereof, are useful as 5-HT1F agonists, single enantiomers and single diastereomers are preferred. Furthermore, while all of the compounds of this invention are useful as 5-HT1F agonists, certain classes are preferred. The following paragraphs describe such preferred classes.
1) Axe2x80x94D is CHxe2x80x94CH2;
2) Axe2x80x94D is Cxe2x95x90CH;
3) R is piperidin-4-yl;
4) R is 1-methylpiperidin-4-yl;
5) R is 1,2,3,6-tetrahydropiperidin-4-yl;
6) R is 1-methyl-1,2,3,6-tetrahydropiperidin-4-yl;
7) R is indolizidin-6-yl;
8) R is [pyrrolidin-2-yl]methyl;
9) R1 is hydrogen;
10) R1 is methyl;
11) Ar is phenyl;
12) Ar is substituted phenyl;
13) Ar is 4-fluorophenyl;
14) Ar is heteroaryl;
15) Ar is selected from the group consisting of furanyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, and pyridazinyl;
16) Ar is substituted heteroaryl;
17) R2 is hydrogen;
18) R2 is methyl;
19) the compound is an acid addition salt;
20) the compound is the hydrochloride salt;
21) the compound is the oxalate salt; and
22) the compound is the fumarate salt.
It will be understood that the above classes may be combined to form additional preferred classes.
It is preferred that the mammal to be treated by the administration of compounds of this invention is human.
The compounds of formula I may be prepared from indoles of formula II as illustrated in Scheme 1 below where A, D, R, R1, and Ar are as defined above and Pg is an amino protecting group. 
Compounds of formula I may be prepared by various arylation methods. One such method is the arylation of silyl enol ethers of methyl ketones with aryl bromides. For a review of this method, see, e.g., JACS, 104:6831-6833, 1982. Such an arylation may be performed by dissolving or suspending a silyl enol ether of formula III, an aryl bromide, of formula II, a catalytic amount of palladium (II), and trialkyltin fluoride. Typical reaction temperatures range from ambient to the reflux temperature of the mixture. Preferably, the reaction is performed at the reflux temperature of the mixture. Typical reaction times range from 1 to about 48 hours but, generally, the reaction is substantially complete after about 5 hours.
Generally, the silyl enol ether is employed in a molar excess relative to the aryl bromide. Such excesses typically range from bout 1.01 to about 1.6 equivalents. Suitable sources of palladium include, but are not limited to Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(Ph2CH2CH2PPh2), PdCl2(P(o-CH3C6H4)3)2, and the like. Generally, about 3 molar percent of palladium is employed.
The skilled artisan would appreciate the need to protect the nitrogen of a compound of formula II during the reaction. For a discussion of optional protecting group, see the definitions provided supra. While the employed protecting group may be removed after the arylation of the a silyl enol, the deprotection step may be performed as desired at any point in the process after arylation.
The compounds of formula VIII and IX, where R is moiety (a), may be prepared substantially as described in U.S. Pat. No. 5,708,008 (""008), the teachings of which are herein incorporated by reference. These syntheses are illustrated below in Scheme 2 where R2, and Ar are as defined above. 
A compound of formula VI may be condensed with a compound of formula VII in the presence of a suitable base to give the corresponding compound of formula VIII. The reaction may be performed by adding the respective compounds of formula VI and VII to a mixture of an appropriate base (typically sodium or potassium hydroxide) in a lower alkanol, typically methanol or ethanol. About 1 to about 5 equivalents of a compound of formula VII, relative to the compound of formula VI are generally employed. A range of about 1.3 to 2.3 equivalents is preferred. The reaction is typically performed for about 0.25 to 24 hours.
If desired, compounds of formula VIII may be hydrogenated over a precious metal catalyst to give the corresponding compounds of formula IX. A catalyst such as sulfided platinum on carbon, platinum oxide, or a mixed catalyst system of sulfided platinum on carbon with platinum oxide may be used to prevent hydrogenolysis of that bromo substituent during the reduction. The hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of 20 p.s.i. to 80 p.s.i., preferably from 50 p.s.i. to 60 p.s.i., at 0xc2x0 C. to 60xc2x0 C., preferably at ambient temperature to 40xc2x0 C., for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate.
Compounds of formula VIII and IX, prepared as described above may be utilized as in Scheme 1.
The compounds of formula VI may be prepared by methods well known to one of ordinary skill in the art, such as that generally described in U.S. Pat. No. 4,443,451, the teachings of which are hereby incorporated by reference. While these indoles are generally commercially available, their preparations are also described in Robinson, The Fischer Indole Synthesis, Wiley, N.Y., 1983; Hamel, et al., Journal of Organic Chemistry, 59:6372, 1994; and Russell, et al., Organic Preparations and Procedures International, 17:391, 1985.
The compounds of formula XI and XII, where R is moiety (c), may be prepared substantially as described in U.S. Pat. No. 5,708,008 (""008), the teachings of which are herein incorporated by reference. These syntheses are illustrated below in Scheme 3 where R2, R3, R4 and Ar are as defined above. 
A compound of formula VI may be condensed with a compound of formula X in the presence of a suitable base to give the corresponding compound of formula XI. The reaction may be performed by adding the respective compounds of formula VI and X to a mixture of an appropriate base (typically sodium or potassium hydroxide) in a lower alkanol, typically methanol or ethanol. About 1 to about 5 equivalents of a compound of formula X, relative to the compound of formula VI are generally employed. A range of about1.3 to 2.3 equivalents is preferred. The reaction is typically performed for about 0.25 to 24 hours.
If desired, compounds of formula XI may be hydrogenated over a precious metal catalyst to give the corresponding compounds of formula XII. A catalyst such as sulfided platinum on carbon, platinum oxide, or a mixed catalyst system of sulfided platinum on carbon with platinum oxide may be used to prevent hydrogenolysis of that bromo substituent during the reduction. The hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of 20 p.s.i. to 80 p.s.i., preferably from 50 p.s.i. to 60 p.s.i., at 0xc2x0 C. to 60xc2x0 C., preferably at ambient temperature to 40xc2x0 C., for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate.
Compounds of formula XI and XII, prepared as described above may be utilized as in Scheme 1.
Compounds of formula VIII may be prepared from methylvinyl ketone and an appropriate amino-dialkylacetal or cyclic acetal according to the procedures found in Tet. Let., 24:3281, 1983, and J.C.S. Perk. I, 447, 1986. These acetals are generally commercially available or can be synthesized by well known methods in the art from their corresponding commercially available 4-substituted butanals or 5-substituted pentanals. This chemistry is illustrated in Scheme 4, R7 and R8 are C1-C4 alkyl or R7 and R8 taken together with the oxygen atoms, to which they are attached, form a 5 or 6 membered cyclic acetal, and n is 0, 1, or 2. 
Compounds of formula IX may be prepared by acid treatment of the addition product of methyl vinyl ketone and a compound of formula XIV. A diethylacetal of formula XIV is a preferred starting material for this reaction (R9 and R10 are ethyl). The reaction may be performed by first dissolving an appropriate aminoacetal of formula XIV in an suitable solvent, typically diethyl ether at 0xc2x0 C., and then adding approximately 1.7 equivalents of methyl vinyl ketone. Typically the reaction is allowed to stir at 0xc2x0 C. for approximately 2 hours before acidification by addition of, or extraction with, aqueous hydrochloric acid. Typically, the organic layer is removed before heating the aqueous layer to approximately 100xc2x0 C. for 1 hour. The resulting 7-octahydroindolizinone, 2-octahydro-2H-quinolizinone, or 4-(1-azabicyclo[5.4.0]undecan)ones of formula IX may be isolated from the reaction mixture by adjusting the pH of the solution to alkaline and extracting with a water immiscible solvent such as ethyl acetate or dichloromethane.
Compounds of formula IX prepared as described in Scheme 4 are racemic and, if used as described in Schemes 3, will produce racemic compounds of the invention. Compounds of the invention that are optically enhanced in one enantiomer may be obtained by resolving the compounds of formula IX before use of these compounds as described in Scheme 3. Methods of resolving enantiomeric compounds of this type are well known in the art. For example, resolution can be achieved by use of chiral chromatography. Furthermore, racemic compounds of formula IX may be converted to their corresponding diastereomeric mixture of salts by reaction with a chiral acid such as (+) or (xe2x88x92) tartaric acid. The diastereomers may then be separated and purified by recrystallization. Once separated, the salts may each be converted back to the chiral free base compounds of formula IX by reacting the salts with an aqueous base, such as sodium hydroxide, then extracting the mixture with a common organic solvent. The optical purity in resolved compounds of formula IX is maintained while undergoing the chemistry described in this application to afford optically pure compounds of the invention. As an alternative, when advantageous, the resolution techniques just discussed may be performed at any convenient point in the syntheses described in Schemes 3.
Compounds of formula VI, VII, and XIV are known in the art and, to the extent not commercially available, are readily synthesized by standard procedures commonly employed in the art such as those described herein.
The optimal time for performing the reactions of Schemes 1-4 may be determined by monitoring the progress of the reaction via conventional chromatographic techniques, e.g., thin layer chromatography and high performance liquid chromatography. Furthermore, it is usually preferred to conduct the reactions of Scheme 1-4 under an inert atmosphere, such as, for example, argon, or, particularly, nitrogen. Choice of solvent is generally not critical so long as the solvent employed is inert to the ongoing reaction and sufficiently solubilizes the reactants to effect the desired reaction. The intermediate compounds of this invention are preferably purified before their use in subsequent reactions. The intermediates and final products may be purified when, if in the course of their formation, they crystallize out of the reaction solution. In such a situation, the precipitate may be collected by filtration and washed with an appropriate solvent. Certain impurities may be removed from the organic reaction mixture by aqueous acidic or basic extraction followed by removal of the solvent by extraction, evaporation, or decantation. The intermediates and final products of formula I may be further purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or alumina.
The following Preparations and Examples are provided to better elucidate the practice of the present invention and should not be interpreted in any way as to limit the scope of same. Those skilled in the art will recognize that various modifications may be made while not departing from the spirit and scope of the invention.